Arylsulfonylformamidoximes

ABSTRACT

ARE USEFUL AS ANTIMICROBIAL AGENTS, HYPOGLYCEMIC AGENTS AND ANTIINFLAMMATORY AGENTS.   Arylsulfonylformamidoximes of the general formula

O United States Patent 1 1 1111 3,880,907

Treuner Apr. 29, 1975 [54] ARYLSULFONYLFORMAMIDOXIMES 3.420.847 1/1969Bell 260/3263 [75] Inventor: Uwe D. Treuner, Regensburg, FOREIGN PATENTSOR APPLICATIONS Germany 2.248.941 10/1973 Germany [73] Assignee: E. R.Squibb & Sons, Inc.,

p i N Primary E.\'uminer.lohn F. Terapane Attorney, Agent, or Ft'rmLawrence S. Levinson;

F1led: Mar. 16, Merle [21] Appl. No.: 342,019

Related U.S. Application Data [57] ABSTRACT {62] Division Of SCI. NO.190.693. OCI. 19. 1971. Pat. NO. Arylsulfonylformamldoxmes ofthe genela'formula NOR {521 U.S. Cl. 260/470; 260/518; 424/248; 424/250; 424/267;424/309; 424/319;

[51] Int. Cl. C07c 147/06; C07c 147/12 [58] Field of Search 260/470, 518R, 518 A [56] References Cited are useful as antimicrobial agents,hypoglycemic UNITED STATES PATENTS agents and antiinflammatory agents.

3.354.174 l l/l967 Bell 260/3092 6 Claims, N0 DrawingsARYLSULFONYLFORMAMIDOXIMES This application is a division of applicationSer. No. 190,693, filed Oct. 19, 1971, now US. Pat. No. 3,736,356.

BRIEF SUMMARY OF THE INVENTION This invention relates to newarylsulfonylformamidoximes having the general formula NOR R is phenyl orlower alkyl; X is halogen; Y is CH 0, S, Nl-l or N-lower alkyl; m is lto 4; and n is 1 to 3 and salts of the basic, salt forming members.

DETAILED DESCRIPTION OF THE INVENTION In formula I, the lower alkylgroups represented by the symbols are straight and branched chainaliphatic hydrocarbon radicals of up to eight carbon atoms such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tbutyl, amyl and thelike. The lower alkanoylamido groups contain the acyl radicals of thelower fatty acids, i.e., up to eight carbon atoms, including, forexample, acetamido, propionamido, butyramido, isobutyramido and thelike. The halogens are chlorine, bromine and iodine, preferably chlorineand bromine, especially the first. The aryl groups are monocycliccarbocyclic aryl, i.e., phenyl.

A preferred group of arylsulfonylformamidoximes within the above classhave the formula NOR @- so -c R is phenyl;

X is chlorine;

m is l or 2; and

n is l.

The compounds of formula I wherein R is a basic group form acid additionsalts with the common organic and inorganic acids. Particularly theseare compounds of formula I wherein R is one of the nitrogen containingradicals.

These salts are acid addition salts formed from a variety ofpharmaceutically acceptable inorganic and organic acids, for example,hydrohalides (especially hydrochloride and hydrobromide), sulfate,nitrate, borate, phosphate, oxalate, tartrate, malate, citrate, acetate,ascorbate, succinate, benzenesulfonate, methanesulfonate,cyclohexanesulfamate and toluenesulfonate. The acid addition saltsfrequently provide a convenient means for isolating the product, e.g.,by forming and precipitating the salt in an appropriate menstruum inwhich the salt is insoluble, then after separation of the salt,neutralizing with a base such as barium hydroxide or sodium hydroxide,to obtain the free base of formula I. Other salts may then be formedfrom the free base by reaction with an equivalent of acid.

The new compounds of formula I wherein R is hydrogen are produced fromphenylsulfonyl cyanides of the formula by treatment with hydroxylamineor a salt thereof, e.g., a hydrohalide such as the hydrochloride. Thereaction is effected in an inert organic solvent, e.g., an alcohol suchas ethanol, at about room temperature. If a hydroxylamine salt is usedan alkali metal bicarbonate such as potassium bicarbonate is preferablypresent.

The phenylsulfonylformamidoxime, which is the product of the abovereaction, may then be converted to a compound of the invention wherein Ris other than hydrogen by reacting that product with an acid anhydride,as for example in Examples 5 and 6 which follow, or with acid halides ormixed acid ester halides as in Examples 7 and 8 which follow or with anisocyanate as in Example 10. The examples further illustrate theconditions of operation which are typical for the formation of thosetypes of products.

The starting materials of formula III may be obtained by any of severalmethods available in the literature, e.g., a benzenesulfinic acid of theformula will react with phenyl cyanate, or a salt of a benzenesulfinicacid having the formula SozNa can be treated with cyanogen bromide, or achloroperbenzoic acid of the formula will react with a benzene orsubstituted benzene of the See, for example, Cox et al., TetrahedronLetters No. 39, 3351-3352 (1969); Pews et al., Jour. Chem. Soc. (Sec D,Chem. Commun.) l969, 1187.

The new compounds of Formula I are useful as antimicrobial agents andmay be used to combat infections in animal species, such as mice, rats,dogs, guinea pigs and the like, due to organisms such as Trichomonasvaginalis, Trichomonas foetus, Staphylococcus aureus, Salmonellaschottmuelleri, Klebsiella pneumoniae, Proteus vulgaris, Escherichiacoli or Trichophyton mentagrophytes. For example, a compound or mixtureof compounds of formula I or pharmaceutically acceptable acid additionsalt (when formed) thereof may be administered orally to an infectedanimal, e.g., to a mouse, in an amount of about to 25 mg. per kg. perday in 2 to 4 divided doses. These may be conventionally formulated in atablet, capsule or elixir containing about to 250 mg. per dosage unit,by compounding the active substance or substances with the conventionalexcipient, vehicle, binder, preservative, flavor, etc., as called for byaccepted pharmaceutical practice. They may also be applied topically,e.g., to dermatophytosis in a guinea pig, in a lotion, salve or cream ata concentration of about 0.01 to 3 percent by weight.

They may also be used as surface disinfectants. About 0.01 to 1 percentby weight of any of these substances may be dispersed on an inert solidor in a liquid such as water and applied as a dust or spray. They may beincorporated also, for example, in a soap or other cleansing agent,e.g., a' solid or liquid detergent, detergent composition, for example,in general cleaning, in cleaning dairy barns or equipment or cleaningfood handling or processing equipment.

The compounds of this invention are also hypoglycemic agents which areeffective in lowering blood sugar content in mammalian species such asmice, rats, rabbits, dogs or the like in a manner analogous totolbutamide. Some are particularly noteworthy in their long duration ofaction. For this purpose a compound or mixture of compounds of formulaI, or non-toxic, physiologically acceptable acid addition salt (whenformed) may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided daily doses, provided on a basis ofabout 1 to 50 mg. per kilogram per day, preferably about 2 to mg. perkilogram per day, is appropriate. These may be conventionally formulatedin an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional vehicle, excipient, binder,preservative, stabilizer, flavor or the like as called for acceptedpharmaceutical practice.

The new compounds of this invention also have antiinflammatoryproperties and are useful as antiinflammatory agents, for example, toreduce local inflammatory conditions such as those of an edematousnature or resulting from proliferation of connective tissue in variousmammalian species such as rats, dogs and the like when given orally indosages of about 5 to 50 mg./kg./day, preferably 5 to 25 mg./kg./day, insingle or two to four divided doses, as indicated by the carageenanedema assay in rats. The active substance may be utilized incompositions such as tablets, capsules, solutions or suspensionscontaining up to about 300 mg. per

unit of dosage of a compound or mixture of compounds of formula I orphysiologically acceptable acid addition salt (when formed). They may becompounded in conventional manner with a physiologically acceptablevehicle or carrier, excipient, binder, preservative, stabilizer, flavor,etc. as called for by accepted pharmaceutical practice. Topicalpreparations containing about 0.01 to 3 percent by weight of activesubstance in a lotion, salve or cream may also be use.

The following examples are illustrative of the invention. Alltemperatures are expressed on the centigrade scale. Additionalvariations of the invention within the scope of formula I may be madeaccording to the following procedures by suitable variations of thestarting materials.

EXAMPLE 1 l-( Phenylsulfonyl )formamidoxime 0.76 g. (12 mmol.) ofhydroxylamine hydrochloride are added to 1.6 g. (10 mmol.) ofbenzenesulfonyl cyanide in 15 ml. of absolute ethanol. The mixture isstirred at room temperature and l .05 g. l2 mmole) of sodium bicarbonateare added in small portions. This is stirred for about 2 hours, theprecipitate is filtered under suction and then washed thoroughly withwater. The addition of water to the ethanolic filtrate yields additionalproduct. The crude product is crystallized from n-butanol. 1 gm. ofwhite crystalline l-(phenylsulfonyl)formamidoxime is obtained, m.p. 108(explosive).

EXAMPLE 2 l-( p-Chlorophenylsulfonyl )formamidoxime White crystallinel-(p-chlorophenylsulfonyl)formamidoxime, m.p. 7375 (dec.) is obtained bythe procedure of Example 1 by substituting an equivalent amount ofp-chlorophenylsulfonyl cyanide for the benezenesulfonyl cyanide.

EXAMPLE 3 l-( p-Toluenesulfonyl )formamidoxime White benzenesulfonyll-(p-toluenesulfonyl)formamidoxime, m.p. 83 (dec.) is obtained by theprocedure of Example 1 by substituting an equivalent amount ofp-toluenesulfonyl cyanide for the benezenesulfonyl cyanide.

EXAMPLE 4 l-[ (p-Acetamidophenyl)sulfonyl]formamidoxine Whitecrystalline l-[ (p-acetamidophenyl)sulfonyl]- formamidoxime m.p., (dec.)is obtained by the procedure of Example 1 by substituting an equivalentamount of (p-acetamidophenyl)sulfonyl cyanide for the benzenesulfonylcyanide.

EXAMPLE 5 EXAMPLE 6 l-( Phenylsulfonyl )formamidoxime-O-succinic monoester 2 g. (10 mmol.) of 1-(phenylsulfonyl)formamidoxime are dissolvedin 50 ml. of dioxane and refluxed for 1 hour with 1.2 g. (12 mmol.) ofsuccinic anhydride. The white product l-(phenylsulfonyl)formamidoxime-O-succinic acid monoester, crystallizes and is recrystallized in theform of white crystals from methyl glycol, m.p. l76-l78.

acid

EXAMPLE 7 l-( Phenylsulfonyl )formamidoxime-O-malonic methyl ester 5 g.(25 mmol.) of l-(phenylsulfonyl)formamidoxime are dissolved in 100 ml.of absolute dioxane, treated with 3.2 g. (40 mmol.) of pyridine and 5 g.(25 mmol.) of malonic acid methyl ester chloride are slowly addeddropwise with stirring and cooling. The progress of the reaction isfollowed with thin layer chromatography. At the end of the reaction, thesolvent is removed under vacuum and the residue is taken up with water,whereupon the product crystallizes. The product,l-(phenylsulfonyl)formamidoxime-O-malonic acid methyl ester, isrecrystallized from ethanol to obtain 2 g. of cream colored crystals,m.p. l56-l59 (dec.).

acid

EXAMPLE 8 1-( Phenylsulfonyl )-O-( 4- chlorobutyryl)formamidoxime 2.0 g.(10 mmol.) of 1-(phenylsulf0nyl)formamidoxime and 0.8 g. (10 mmol.) ofpyridine are dissolved in ml. of tetrahydrofuran and 1.55 g. l 1 mmol.)of 4- chlorobutyryl chloride are added slowly dropwise with stirring.After a short time, the product, 1- phenylsulfonyl )-O-( 4-chlorobutyryl)formamidoxime, crystallizes. It is recrystallized from methyl glycol toobtain 3 g. of white needles, m.p. 185 (dec.).

EXAMPLE 9 1-( Phenylsulfonyl )-O-(trichloroacetyl )formamidoxime l-(Phenylsulfonyl )-O-( trichloroacetyl )formamidoxime, m.p. (dec.) isobtained by the procedure of Example 5 by substituting an equivalentamount of trichloroacetic anhydride for the chloracetic anhydride.

EXAMPLE l0 1-(Phenylsulfonyl)formamidoxime-O-carbanilate 2 g. (20 mmol.)of l-(phenylsulfonyl)formamidoxime are dissolved in 25 ml. of toluenetreated with 1.2 g. of phenylisocyanate and refluxed for 1 hour. 1.9 g.of a white crystalline l (phenylsulfonyl)formamidoxime-O-carbanilate areobtained as a precipitate which is recrystallized from methylglycol-water, m.p. 193 (dec.).

The following additional compounds are prepared by the method of Example1 and 5 by substituting for the benzenesulfonyl cyanide theappropriately substituted analog in the procedure of Example 1 and thenusing the product thus obtained in the procedure of Example 5,substituting for the chloracetic anhydride the appropriately substitutedacid anhydride NOR Q C (R y] NH Example R R n 1 11 E CH CH H l2 C-CH BrH l l 13 c cc1 p CH l 14 c CH COOC H H l 15 f! CH COOC H p CH l 16 C CH.COOC H p C H CONH Continued Example R R n 17 z-cu -coocn p-Cl 1 18 c-cH -QC H 3, 4, s-cn 3 19 C-CH -o 20 C CH N O 1 ll 2 H O 21- l(|ICH -NN-CH H l 22 -cn -cl pCI-I -O-Cl 2 23 C CH N NH 25 C-CH -N S H l 26 iI-CHCH2 S CH3 H c 1 27 fi-CH CH2 SQ H 1 (also -c -NH 29 H2 2 P 3 HCl salt l30 iC)CH CH NHC H H l 31 lCCH N (CH3)2 H 32 Cg-CHCH H l i 2 33 ("f-NHC Ho,p C1

What is claimed is: and pharmaceutically acceptable salts thereof. 1. Acompound of the formula 2. A compound as in claim 1 wherein m is l or 2and NOR n iS l.

3. A compound as in claim 1 wherein R is COO- Q'SO C lower alkyl.

4. A compound as in claim 1 wherein R is COCH- (R NH COOCH R is hydrogenand n is l.

1 n 2 5. A compound as in claim 1 wherein R is COOH. h in R is 2)m 2; 1is y g a g 6. A compound as in claim 1 wherein R is lower alkyl or loweralkanoylamido; R is COOH or CO(CH COOH, R is hydrogen and n is 1,COO-lower alkyl; m is l to 4; and n is l to 3,

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein m is 1or 2 and n is
 1. 3. A compound as in claim 1 wherein R2 is COO-loweralkyl.
 4. A compound as in claim 1 wherein R is -COCH2COOCH3, R1 ishydrogen and n is
 1. 5. A compound as in claim 1 wherein R2 is COOH. 6.A compound as in claim 1 wherein R is -CO(CH2)2COOH, R1 is hydrogen andn is 1.